Iatrogenic hypoglycemia is a fact of life for people with type 1 diabetes aiming for optimal glycemic control. By impairing the body's defenses against hypoglycemia, iatrogenic hypoglycemia creates vicious circle that may ultimately lead to hypoglycemia unawareness. Hypoglycemia unawareness carries the risk of prolonged hypoglycemia with the consequence of loss of normal behavior and brain damage, and hence is feared by both patients and their relatives a major defect in the pathogenesis of hypoglycemia unawareness is the failure of the brain to sense hypoglycemia. This defect may be explained by the brain's apparent ability to maintain its metabolic function despite a fall in glucose supply, for example by increasing blood to brain glucose transport. Studies that have investigated the role of increased brain glucose transport in the development of hypoglycemia unawareness, however, have found opposing results. We hypothesize that any alteration in the balance between glucose delivery, uptake and metabolism on the one hand and global cerebral metabolic demand on the other, while initially neuroprotective, can contribute to the glucose sensing defect and thus to hypoglycemia unawareness. The specific neuroprotective, can contribute to the glucose sensing defect and thus to hypoglycemia unawareness. The specific aims of these projects are: 1) to determine, in vivo, the effect of acute hypoglycemia on brain glucose uptake and intracellular glucose metabolism, cerebral blood flow and on global cerebral metabolic rate (metabolic demand), in non-diabetic humans; and 2) to determine whether recurrent hypoglycemia changes these parameters of brain glucose handling, cerebral blood flow or cerebral metabolic rate, and whether such changes translate into the clinical syndrome of hypoglycemia unawareness. To measure brain glucose metabolism in vivo, we will apply Magnetic Resonance Spectroscopy (MRS) techniques at a field strength of 3 tesla to assess brain glucose handling, energy metabolism, and cerebral perfusion. The long-term objective of this project is to find new targets that allow a more problem-oriented approach to manage and/or reverse hypoglycemia unawareness.